Vaccines containing antigens from more than one pathogenic organism within a single dose are known as “multivalent” or “combination” vaccines. Various combination vaccines have been approved for human use in the EU and the USA, including trivalent vaccines for protecting against diphtheria, tetanus and pertussis (“DTP” vaccines) and trivalent vaccines for protecting against measles, mumps and rubella (“MMR” vaccines).
Combination vaccines offer patients the advantage of receiving a reduced number of injections, which leads to the clinical advantage of increased compliance (e.g. see chapter 29 of reference 1), particularly for pediatric vaccination. At the same time, however, they present manufacturing difficulties due to factors including: physical and biochemical incompatibility between antigens and other components; immunological interference; and stability.
The inclusion of non-antigen components in vaccines is necessary, but can cause difficulties. Surfactants are a particular problem in combination vaccines because one antigen may require a surfactant for optimal activity, whereas another may be negatively affected by the surfactant's presence. Furthermore, the inclusion of surfactants in pediatric vaccines is of concern to some patient groups, even though the surfactant may be generally accepted as safe.
Of particular interest in the vaccine field are the polyoxyethylene sorbitan esters surfactants, especially the polysorbate 20 (also known as ‘Tween 20’, or polyoxyethylene sorbitan monolaurate) and polysorbate 80 (also known as ‘Tween 80’, or polyoxyethylene sorbitan monooleate) species. Polysorbate 20 is found in the monovalent HAVRIX™ inactivated hepatitis A vaccine, and polysorbate 80 is found in combination vaccines such as TRIPEDIA™ and the INFANRIX™ series of vaccines, both of which include diphtheria and tetanus toxoids, and acellular pertussis. These two surfactants have also been used to stabilise liquid rotavirus vaccines [2].
The polysorbates have also been used in the manufacture of combination vaccines that contain hepatitis B surface antigen (‘HBsAg’) e.g. references 3 & 4 disclose a process for making a tetravalent D-T-P-HBsAg vaccine in which interference with the phospholipid component of the HBsAg is avoided by adding a non-ionic surfactant such as Tween 20, Tween 80 or Triton X-100. The data in FIG. 2 of refs. 3 & 4 (FIG. 1 herein) show that surfactant is required for maintaining HBsAg antigenicity, but is less important for the other components. The highest surfactant concentration tested was 10 μg/ml with 20 μg/ml HBsAg, and this also gave the best antigenicity.
In the process of references 3 and 4, the non-ionic detergent is added after the HBsAg has been purified. Adding detergents after purification of HBsAg is not optimal, however, as it requires a separate processing step during manufacture, which increases the processing time and also increases the risk of introducing contamination into the HBsAg. If a contaminated component is used when making a combination vaccine then the eventual loss is greater than when making monovalent vaccines e.g. if a contaminated HBsAg component is mixed with a clean D-T-P component then the whole D-T-P-HBsAg mixture has to be scrapped, rather than only the HBsAg.
For combination vaccines containing non-ionic surfactants, therefore, there remains a need for a manufacturing processes in which the surfactant does not have to be added as a separate component during the process.